Aging-associated cognitive decline has serious public health and economic consequences, which will increase as the percentage of aged Americans rises. Thus far there is little effective treatment to combat this problem, in part because the underlying causes remain unclear. The aged mammalian brain exhibits evidence of cell cycle de-regulation and aberrant cell cycle re-entry of postmitotic cells in the brain has been proposed to be both a cause and a consequence of neurodegeneration. Most of the research on cell cycle re-entry in the aging brain has been limited to correlative studies due to difficulty in obtaining aged samples, inconsistencies in measuring cell cycle re-entry and difficulty in manipulating cell cycle regulators specifically in the brain during aging in mammalian model systems. We have observed that the brain of the fruit fly Drosophila melanogaster exhibits evidence of age-associated cell cycle re-entry and this project seeks to establish Drosophila as a genetically tractable and quickly aging model system to study and manipulate cell cycle re-entry in the aging brain. In Aim 1, we establish when and where cell cycle re-entry occurs in the aged fly brain, under normal physiological aging conditions. In Aim 2, we determine the biological outcomes of manipulating cell cycle re-entry in the brain on aging phenotypes. Successful completion of the proposed work will establish a new genetically tractable model system to study the relationship of aging and cell cycle re-entry in the brain and resolve the cause-effect relationship of cell cycle re-entry in the brain and behavioral decline with age. This research may indicate new avenues to treat aging related neural decline by targeting cell cycle machinery. Longer-term future directions for this research will include filling in the molecular details that link aging and cell cycle de-regulation in the brain.